Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

Honglian Liu; Yingyin Liao; Fei Yu; Leo Ngo Shing Li; Yajie Zhang; Lin Zhu; Guangshan Xie; Jiayan Liu; Siwen Liu; Shaofeng Deng; Rachel Chun Yee Tam; Wenjun Song; Pin Chen; Xiaofeng Huang; Conor J. Cremin; Yixin Chen; Min Zheng; Pui Wang; Zongwei Cai; Kwok Yung Yuen; Honglin Chen; Bobo Wing Yee Mok

doi:10.1016/j.isci.2025.113391

Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

Honglian Liu, Yingyin Liao, Fei Yu, Leo Ngo Shing Li, Yajie Zhang, Lin Zhu, Guangshan Xie, Jiayan Liu, Siwen Liu, Shaofeng Deng, Rachel Chun Yee Tam, Wenjun Song, Pin Chen, Xiaofeng Huang, Conor J. Cremin, Yixin Chen, Min Zheng, Pui Wang, Zongwei Cai, Kwok Yung YuenHonglin Chen, Bobo Wing Yee Mok^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

Abstract

Interferon (IFN)-dependent responses constitute a critical initial defense against viruses in mammalian cells, while RNA interference (RNAi) acts as an additional strategy to combat invading viral pathogens. Investigating the functionality of mammalian Argonaute 2 (AGO2), an essential component of the RNA-induced silencing complex, we found it to negatively modulate influenza A virus infection-induced RIG-I-mediated antiviral signaling. AGO2 depletion in human cell lines significantly enhanced the RNA virus-triggered phosphorylation of IRF3 and downstream antiviral gene activation. Interestingly, this negative regulation occurred independently of gene silencing via canonical RNA silencing pathways and instead involved the binding of AGO2 to viral RNA molecules carrying 5′-triphosphates or cytosolic RIG-I agonists. These findings highlight AGO2’s crucial role in balancing antiviral signaling activation and restricting virus infection to prevent excessive immune responses.

Original language	English
Article number	113391
Number of pages	21
Journal	iScience
Volume	28
Issue number	9
Early online date	2 Sept 2025
DOIs	https://doi.org/10.1016/j.isci.2025.113391
Publication status	Published - 19 Sept 2025

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Biological sciences
Microbiology
Natural sciences
Pharmacology
Virology

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Liu, H., Liao, Y., Yu, F., Li, L. N. S., Zhang, Y., Zhu, L., Xie, G., Liu, J., Liu, S., Deng, S., Tam, R. C. Y., Song, W., Chen, P., Huang, X., Cremin, C. J., Chen, Y., Zheng, M., Wang, P., Cai, Z., ... Mok, B. W. Y. (2025). Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding. iScience, 28(9), Article 113391. https://doi.org/10.1016/j.isci.2025.113391

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title = "Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding",

abstract = "Interferon (IFN)-dependent responses constitute a critical initial defense against viruses in mammalian cells, while RNA interference (RNAi) acts as an additional strategy to combat invading viral pathogens. Investigating the functionality of mammalian Argonaute 2 (AGO2), an essential component of the RNA-induced silencing complex, we found it to negatively modulate influenza A virus infection-induced RIG-I-mediated antiviral signaling. AGO2 depletion in human cell lines significantly enhanced the RNA virus-triggered phosphorylation of IRF3 and downstream antiviral gene activation. Interestingly, this negative regulation occurred independently of gene silencing via canonical RNA silencing pathways and instead involved the binding of AGO2 to viral RNA molecules carrying 5′-triphosphates or cytosolic RIG-I agonists. These findings highlight AGO2{\textquoteright}s crucial role in balancing antiviral signaling activation and restricting virus infection to prevent excessive immune responses.",

keywords = "Biological sciences, Microbiology, Natural sciences, Pharmacology, Virology",

author = "Honglian Liu and Yingyin Liao and Fei Yu and Li, {Leo Ngo Shing} and Yajie Zhang and Lin Zhu and Guangshan Xie and Jiayan Liu and Siwen Liu and Shaofeng Deng and Tam, {Rachel Chun Yee} and Wenjun Song and Pin Chen and Xiaofeng Huang and Cremin, {Conor J.} and Yixin Chen and Min Zheng and Pui Wang and Zongwei Cai and Yuen, {Kwok Yung} and Honglin Chen and Mok, {Bobo Wing Yee}",

note = "This study is partly supported by Health@InnoHK, Innovation and Technology Commission, the Theme-Based Research Scheme (T11-709/21-N), the Collaborative Research Fund (C5110-20GF), and the General Research Fund (17107019) of the Research Grants Council, the Health and Medical Research Fund Commissioned Research on COVID-19 (COVID1903010, COVID190123) and HMRF (19181052 and 14131032), Hong Kong, the Tier 1 Research Start-up Grants from the Research Committee of Hong Kong Baptist University (162874), the Hong Kong Special Administrative Region, China, the Emergency Collaborative Project (EKPG22-01) of Guangzhou Laboratory, China, and the Shenzhen Science and Technology Program (JCYJ20240813145001002). Publisher Copyright: {\textcopyright} 2025 The Authors",

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doi = "10.1016/j.isci.2025.113391",

language = "English",

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T1 - Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

AU - Liu, Honglian

AU - Liao, Yingyin

AU - Yu, Fei

AU - Li, Leo Ngo Shing

AU - Zhang, Yajie

AU - Zhu, Lin

AU - Xie, Guangshan

AU - Liu, Jiayan

AU - Liu, Siwen

AU - Deng, Shaofeng

AU - Tam, Rachel Chun Yee

AU - Song, Wenjun

AU - Chen, Pin

AU - Huang, Xiaofeng

AU - Cremin, Conor J.

AU - Chen, Yixin

AU - Zheng, Min

AU - Wang, Pui

AU - Cai, Zongwei

AU - Yuen, Kwok Yung

AU - Chen, Honglin

AU - Mok, Bobo Wing Yee

N1 - This study is partly supported by Health@InnoHK, Innovation and Technology Commission, the Theme-Based Research Scheme (T11-709/21-N), the Collaborative Research Fund (C5110-20GF), and the General Research Fund (17107019) of the Research Grants Council, the Health and Medical Research Fund Commissioned Research on COVID-19 (COVID1903010, COVID190123) and HMRF (19181052 and 14131032), Hong Kong, the Tier 1 Research Start-up Grants from the Research Committee of Hong Kong Baptist University (162874), the Hong Kong Special Administrative Region, China, the Emergency Collaborative Project (EKPG22-01) of Guangzhou Laboratory, China, and the Shenzhen Science and Technology Program (JCYJ20240813145001002). Publisher Copyright: © 2025 The Authors

PY - 2025/9/19

Y1 - 2025/9/19

N2 - Interferon (IFN)-dependent responses constitute a critical initial defense against viruses in mammalian cells, while RNA interference (RNAi) acts as an additional strategy to combat invading viral pathogens. Investigating the functionality of mammalian Argonaute 2 (AGO2), an essential component of the RNA-induced silencing complex, we found it to negatively modulate influenza A virus infection-induced RIG-I-mediated antiviral signaling. AGO2 depletion in human cell lines significantly enhanced the RNA virus-triggered phosphorylation of IRF3 and downstream antiviral gene activation. Interestingly, this negative regulation occurred independently of gene silencing via canonical RNA silencing pathways and instead involved the binding of AGO2 to viral RNA molecules carrying 5′-triphosphates or cytosolic RIG-I agonists. These findings highlight AGO2’s crucial role in balancing antiviral signaling activation and restricting virus infection to prevent excessive immune responses.

AB - Interferon (IFN)-dependent responses constitute a critical initial defense against viruses in mammalian cells, while RNA interference (RNAi) acts as an additional strategy to combat invading viral pathogens. Investigating the functionality of mammalian Argonaute 2 (AGO2), an essential component of the RNA-induced silencing complex, we found it to negatively modulate influenza A virus infection-induced RIG-I-mediated antiviral signaling. AGO2 depletion in human cell lines significantly enhanced the RNA virus-triggered phosphorylation of IRF3 and downstream antiviral gene activation. Interestingly, this negative regulation occurred independently of gene silencing via canonical RNA silencing pathways and instead involved the binding of AGO2 to viral RNA molecules carrying 5′-triphosphates or cytosolic RIG-I agonists. These findings highlight AGO2’s crucial role in balancing antiviral signaling activation and restricting virus infection to prevent excessive immune responses.

KW - Biological sciences

KW - Microbiology

KW - Natural sciences

KW - Pharmacology

KW - Virology

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UR - https://www.sciencedirect.com/science/article/pii/S2589004225016529?via%3Dihub

U2 - 10.1016/j.isci.2025.113391

DO - 10.1016/j.isci.2025.113391

M3 - Journal article

AN - SCOPUS:105014604189

SN - 2589-0042

VL - 28

JO - iScience

JF - iScience

IS - 9

M1 - 113391

ER -

Argonaute 2 inhibits RIG-I signaling via competition for viral RNA binding

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